Delivery devices that allow remote, repeatable, and reliable switching of drug flux could have a marked impact on the treatment of a variety of medical conditions. An ideal device for on-demand drug delivery should safely contain a large quantity of drug, release little or no drug in the "off" state, be repeatedly switchable to the "on" state without mechanically disrupting the device, and be triggered non-invasively to release a consistent dosage demanded by a patient (e.g. local pain relief) or prescribed by a doctor (e.g. localized chemotherapy). Despite the clinical need, few such drug delivery devices have been developed and none are available for clinical use. The goal of this application is to develop such a device, that could provide tunable on demand drug release from a reservoir that could be deep within the body, with near-infrared light (NIR) as the trigger. In the near term, this device could be used to treat chronic pain. Our proposed device will consist of a composite membrane containing a disordered network of temperature-sensitive polymer nanoparticles and gold nanoshells. We hypothesize that when the device is irradiated with NIR light at the appropriate wavelength, the gold nanoshells will heat and cause the polymer nanoparticles to collapse, opening pores in the membrane. We intend to validate this design in three phases. First, we will examine both the "on" and "off" state permeability of the membrane to a number of compounds, including tetrodotoxin (TTX), saxitoxin (STX), bupivacaine, and dexamethasone. Second, we will examine its biocompatibility both in vivo and in vitro, through cell culture assays and histological analysis. Finally, we will incorporate this membrane into drug reservoir capsules, and assess the ability of the device to locally deliver anesthesia at the sciatic nerve in a rat model. We will deliver numerous formulations, including cocktails that have been used to achieve sensory-selective nerve blockade, with efficacy assayed using standard techniques to measure numbness in the hind paw of the rat. Taken together, these experiments will help us to assess the clinical applicability of our proposed NIR-triggered membranes. PUBLIC HEALTH RELEVANCE: We propose to develop a biocompatible, implantable capsule capable of releasing drugs on demand, with the patient or physician determining the timing, duration, and size of the dose delivered. Drug release will be triggered by an external light beam that penetrates harmlessly through skin and tissue. One example of an application is chronic pain: the patient could determine when to obtain relief and for how long, as well as the intensity of that relief.